The present invention relates to pharmaceutical compositions containing aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
The non-steroidal anti-inflammatory drugs are a group of compounds which inhibit the biosynthesis of prostaglandins. The group embraces a wide range of chemical structures, but can be subdivided into several general structural types. These types are described in Chapter 5 of "The Clinical Pharmacology of Anti Inflammatory Compounds" by Brooks et al. One general type is based on a carboxylic acid structure while a second is based on enolic acid. Within the first general type are the aspirin-like NSAIDs, which have a structure based on salicylic acid and which include aspirin as well as diflunisal. Also within this general type are those compounds which are structurally related to propionic acid, such as naproxen and ibuprofen, and those related to acetic acid such as diclofenac and indomethacin. The second general type includes pyrazolones such as oxyphenbutazone and oxicams such as piroxicam.
NSAIDs have been extensively used in recent years for the treatment of chronic rheumatic or arthritic conditions and for the management of pain. The compounds are believed to bring relief by inhibiting prostaglandin synthetase at affected joints or in other body tissues. However, the compounds have recently been linked to increased occurrence of gastrointestinal blood loss resulting in anaemia and leading to peptic and duodenal ulcers in patients who use the drugs particularly over long time periods. These adverse reactions have been widely described, both in the press and in the scientific literature. For example, A. and E. Keat in an article in the June 1985 issue of "Update" described the adverse gastrointestinal tract reactions to antirheumatic drugs and in particular they mention that aspirin is known to be responsible for mucosal erosions, blood losses of around 5 ml per day, and for duodenal ulcers. B. J. R. Whittle and J. R. Vane in a paper, Arch. Toxicol, Suppl., 7, 315-322 (1984) considered the biochemical basis for the gastrointestinal toxicity of non-steroid antirheumatoid drugs and the effects of NSAIDs in inducing gastric damage.
In the shorter term, bleeding from the gastrointestinal tract is produced and gradual erosion of the gastric mucosa can lead to subsequent ulceration. These adverse effects on the gastrointestinal tract are believed to have two principal causes. Firstly many of the NSAIDs are chemical irritants which may annoy the gastric mucosa. Secondly, the NSAIDs inhibit prostaglandin synthesis not only in the joints but also, non-specifically, in the gut. Since some prostaglandins have a protective role in the gut, their absence makes the mucosa even more susceptible to damage by irritation.
In an attempt to overcome these drawbacks recent work has aimed at producing NSAIDs which have prostaglandin-like properties. These however have their own associated disadvantages in having secondary effects on smooth muscle activity.
The present inventors have discovered that by treatment with aspirin and an aromatic hydroxysulphonic acid in combination. gastrointestinal bleeding due to the aspirin can be significantly reduced, apparently without the introduction of further side effects.
Such aromatic hydroxysulphonic acids include ethamsylate (also known as cyclonamine). I, dobesilate calcium, II, and 263-E, III, which is the diethylamine salt of persilic acid. The formulae of these three compounds are shown below. ##STR1##
Ethamsylate is a known treatment for a variety of conditions where bleeding occurs from small blood vessels. For example, it has been used to control menorrhagia and bleeding during gynaecological surgery, to control haemorrhage during or after general surgery, to stop nose bleeds and control surgical haemorrhage in ear, nose and throat surgery and to limit or prevent periventricular haemorrhage in low birth weight babies. There have also been suggestions, based on qualitative observations, that ethamsylate may be a useful treatment for bleeding gastric ulcers. No use of ethamsylate in connection with iatrogenically induced bleeding has been mentioned.
The mode of action of ethamsylate is not well understood. Ethamsylate has been suggested to inhibit the operation of some prostaglandins. Work by the present inventors and others suggests that ethamsylate possibly has a selective inhibitory effect on prostaglandins PGF.sub.2 alpha and PGI.sub.2 (R. A. Hutton et al., Thrombosis and Haematosis 56, 6-8 (1986). The related compound 236-E is thought to be a prostaglandin synthetase promoter. Prostaglandins vary in their effects in the body, and a chemical which affects some prostaglandins in a particular manner may have a different or opposite effect on other prostaglandins.
The related compound, dobesilate calcium, is known to affect platelet aggregation and has been shown to inhibit artificially induced thrombus formation in hamster cheek pouches when administered by intraperitoneal injection (M. Michal et al, Thrombosis Research 40, 215-226 (1985). When the dobe-silate calcium was administered by injection in combination with aspirin a synergistic inhibition of thrombus formation was observed.